CLINICAL EPIDEMIOLOGY www.jasn.org

Biliary Tract and Liver Complications in PolycysticKidney Disease

Parminder K. Judge,*†‡ Charlie H.S. Harper,*† Benjamin C. Storey,*†‡ Richard Haynes,*†‡

Martin J. Wilcock,‡ Natalie Staplin,† Raph Goldacre,§ Colin Baigent,*† Jane Collier,|

Michael Goldacre,§ Martin J. Landray,*†§ Christopher G. Winearls,‡ andWilliam G. Herrington†‡

*Medical Research Council–Population Health Research Unit, †Clinical Trial Service Unit and Epidemiological StudiesUnit, and §Big Data Institute, Nuffield Department of Population Health, University of Oxford, Oxford, UnitedKingdom; and ‡Oxford Kidney Unit and |Department of Gastroenterology, Oxford University Hospitals NationalHealth Service Foundation Trust, Oxford, United Kingdom

ABSTRACTPolycystic liver disease is a well described manifestation of autosomal dominant polycystic kidney disease(ADPKD). Biliary tract complications are less well recognized. We report a 50-year single-center experience of1007patients, which raised ahypothesis thatADPKD is associatedwith biliary tract disease.We tested this hypoth-esis using all England Hospital Episode Statistics data (1998–2012), within which we identified 23,454 people withADPKD and 6,412,754 hospital controls. Hospitalization rates for biliary tract disease, serious liver complications,and a range of other knownADPKDmanifestationswere adjusted for potential confounders. Comparedwith non-ADPKD hospital controls, those with ADPKD had higher rates of admission for biliary tract disease (rate ratio [RR],2.24; 95% confidence interval [95%CI], 2.16 to 2.33) and serious liver complications (RR, 4.67; 95%CI, 4.35 to 5.02).In analyses restricted to thoseonmaintenancedialysis orwith a kidney transplant, RRs attenuated substantially, butADPKD remained associatedwith biliary tract disease (RR, 1.19; 95%CI, 1.08 to 1.31) andperhapswith serious livercomplications (RR, 1.15; 95% CI, 0.98 to 1.33). The ADPKD versus non-ADPKD RRs for biliary tract disease werelarger for men than women (heterogeneity P,0.001), but RRs for serious liver complications appeared higher inwomen (heterogeneity P,0.001). Absolute excess risk of biliary tract disease associated with ADPKD was largerthan that for serious liver disease, cerebral aneurysms, and inguinal hernias but less than that for urinary tractinfections. Overall, biliary tract disease seems to be a distinct and important extrarenal complication of ADPKD.

J Am Soc Nephrol 28: 2738–2748, 2017. doi: https://doi.org/10.1681/ASN.2017010084

Autosomal dominant polycystic kidney disease(ADPKD) is the most common inherited kidneydisease.1,2 It is characterized by progressive enlarge-ment of the kidneys with multiple bilateral cystsand eventual loss of kidney function, often causingend-stage renal disease (ESRD) in middle age.1,3

Ten percent of patients on renal replacement ther-apy (RRT) in the United Kingdom and 5% in theUnited States have a primary renal diagnosis ofADPKD.4,5 ADPKD is a multisystem disorder,with polycystic liver being a common extrarenalmanifestation.6–8 The prevalence of liver cysts inpeople with ADPKD increases with age, with.90% of patients aged.40 years old having at leastone cyst.9 Unlike renal cysts (which are unaffected

by sex), liver cysts are more common and numer-ous in premenopausal women with ADPKD thanmen.7,9,10 ADPKD is also associated with other

Received January 25, 2017. Accepted March 24, 2017.

P.K.J., C.H.S.H., C.G.W., and W.G.H. contributed equally to thiswork.

Published online ahead of print. Publication date available atwww.jasn.org.

Correspondence: Dr. William G. Herrington, Clinical Trial Ser-vice Unit and Epidemiological Studies Unit, Richard Doll Build-ing, Roosevelt Drive, Old Road Campus, Oxford, OX3 7LF,United Kingdom. Email: will.herrington@ndph.ox.ac.uk

Copyright © 2017 by the American Society of Nephrology

2738 ISSN : 1046-6673/2809-2738 J Am Soc Nephrol 28: 2738–2748, 2017

abdominal manifestations, including colonic diverticular dis-ease, abdominal wall hernias, and pancreatic cysts.8,10,11 Mildcommon bile duct dilation has also been reported,12 but un-like the much rarer autosomal recessive form of polycystickidney disease, which is associated with nonobstructive intra-hepatic duct dilation (Caroli disease) and recurrent cholangitis,13

clinically significant biliary tract complications are less wellrecognized in ADPKD.

We made an observation at our tertiary center that, in ad-dition to the infective and compressive complications causedby polycystic livers, several patients with ADPKD had repeatedhospitalizations for biliary tract disease. A systematic literaturereview of PubMed from its inception through July 22, 2016identified a total of 662 potentially relevant abstracts, fromwhich 44 full text articles were read and ten relevant reportswere identified (Supplemental Figure 1).12,14–22 These in-cluded six articles reporting obstructive jaundice due to en-larged cysts,17–22 and four reporting six cases of symptomaticcholecystitis, usually with gallstones.12,14–16 We found no re-ports that described the range of presentations of biliary tractdisease in individuals with ADPKD, and we did not find anythat had quantified any excess risk of clinically significant bil-iary tract disease in ADPKD. To explore whether our clinicalobservations reflect a previously undescribed feature ofADPKD, we aimed to report a single tertiary center’s approx-imately 50-year experience of biliary tract disease and seriousliver complications in patients with ADPKD. We then testedthe hypothesis that biliary tract disease is more common inADPKD by using routinely collected English hospital inpa-tient data from 1998 to 2012 to compare hospitalization ratesfor biliary tract disease among people with ADPKD with ratesin non-ADPKD control populations.

RESULTS

Oxford Kidney Unit Case Series 1967–2015Between 1967 and 2015, 1011 patients with polycystic kidneydisease were cared for at the Oxford Kidney Unit, includingfour patients (0.4%) with autosomal recessive polycystic kid-ney disease. Of the 1007 with presumed ADPKD, 35 patientswere identified as having developed biliary tract disease and/or a liver complication (Table 1). We noted that biliary tractdisease was mostly cholecystitis or other gallstone-relatedcomplications and that this was the prominent presentationin 24 patients. Serious liver complications were the prominentpresentation in 11 patients, mostly representing liver cyst in-fections (Table 1). Nine patients developed both biliary tractdisease and a serious liver complication.

The median ages at presentation with biliary tract diseaseand liver complications were 31 (interquartile range, 26–49)years old and 38 (interquartile range, 31–46) years old, respec-tively (Table 1). These complications tended to manifest inpeople with stage 5 chronic kidney disease (CKD), many ofwhom had started maintenance RRT by the time of their first

such presentation. Similar proportions of women and menwere affected by biliary tract disease (13 of 522 women versus11 of 485 men; P=0.82), but women seemed more likely todevelop a serious liver complication (ten of 522 women versusone of 485 men; P=0.01).

Biliary tract infections accounted for 74% (90 of 121) ofbiliary tract presentations and often recurred (there were 90occurrences among the 21 patients with a biliary tract infec-tion). Escherichia coli and Enterococcus species were the mostcommon causes of biliary tract infection. Liver cyst infectionsoccurred in 67% (12 of 18) of those with a serious liver com-plication, accounting for 38% (22 of 58) of all admissions forserious liver complications. Unlike biliary tract infections, themajority of liver infections were culture negative (Supplemen-tal Figure 2). Management of liver cyst infections was usuallywith antibiotic therapy alone, whereas management of biliarytract disease frequently involved both antibiotics and a rangeof radiologic and surgical interventions (Supplemental Table1). Forty-two percent (11 of 26) of patients with biliary tractdisease had gallstones removed at endoscopic retrogradecholangiopancreatography, five patients required sphincterot-omies, and three had biliary stents inserted (SupplementalTable 1).

Disease Association Study Using All England HospitalEpisode Statistics 1998–2012Wedesigned a disease association study using all EnglandHos-pital Episode Statistics (HES) to test the subsequent hypothesisthat biliary tract disease might be more common in ADPKDthanwould be expected comparedwith the general population.

Using data on 43.2 million people aged over 20 years oldwith at least one hospital admission recorded in linked andanonymized all EnglandHES between 1998 and 2012,we iden-tified 23,454 people admitted with a diagnostic code forADPKD who were unlikely to have autosomal recessive poly-cystic kidney disease (Concise Methods). Median age at thestart of follow-upwas 58 years old (44–70), 10,789 (46%)werewomen, and 20,011 (85%) were white (Table 2). A history ofprior diabetes or vascular disease was recorded in 906 (4%)and 1747 (7%), respectively. In comparison, 6,412,754 hospi-tal controls were identified from an admission for one of avariety of minor conditions (with no mention of polycystickidney disease in any admission). Hospital controls were, onaverage, younger (median age =48 [34–67] years old) and lesslikely to have diabetes (189,858; 3%) or vascular disease(181,832; 3%) (Table 2).

After adjustment for age, sex, ethnicity, social deprivation,region, priordiabetes, prior vascular disease or cancer, and yearof first admission, the rates of admission for a series of diseaseoutcomes were compared among people with ADPKD versuswithout ADPKD (referred to as ADPKD versus non-ADPKDrate ratios [RRs]). Compared with hospital controls, adjustedrates of ESRD were 112 times higher in people with ADPKD(2.82% versus 0.03% per year; RR, 112; 95% confidenceinterval [95%CI], 109 to 116) (Figure 1A). Figure 1A provides

J Am Soc Nephrol 28: 2738–2748, 2017 ADPKD and Biliary/Liver Disease 2739

www.jasn.org CLINICAL EPIDEMIOLOGY

Table

1.Baselinech

aracteristicsof

individua

lswithADPK

Dan

deither

abiliarytractor

seriou

sliver

complication:

OxfordKidne

yUnitcase

series

(196

7–20

15)

Sex

Ageat

ADPKD

Diagno

sis,

yr

Timefrom

ADPKDDiagno

sis

toFirstBiliary

Trac

tDisease/

Serious

Live

rComplication,y

r

CKD

Stag

eat

First

BiliaryTrac

tDisease/

Serious

Live

rComplication

BiliaryTrac

tDiseasean

dSe

rious

Live

rComplications

No.o

fAdmissions

withGallbladder

orBile

Duc

tDisease

Gallstones

Eve

rDiagno

sed

No.o

fAdmissions

withLive

rCystInfection

BiliaryTrac

tan

dLive

rDisease

Diagno

sesorProce

dures

W22

225D

18Ye

s0

Cho

lelithiasiswith

complications

Ma

2832

5D14

Yes

1Cho

lelithiasisrequirin

g43

ERCPs

andsp

hinc

terotomy.

Non

obstructiveintrah

epatic

biliarytrac

tduc

tdilatio

nan

dhe

paticfibrosis.Live

rcyst

infection

M48

105T

9Ye

s0

Cho

lelithiasiswith

complications

requirin

gER

CPan

dsp

hinc

terotomy

Wa

1546

5T9

No

1Cho

lelithiasiswith

complications

andliver

abscess

Ma

3426

5T8

Yes

3Biliaryob

structionan

dsepsisdue

toen

larged

liver

cystsan

dgallstone

s.

Cho

lecystec

tomy.

Cystderoo

fing

.Liver

cyst

infections

M18

445T

7Ye

s0

Cho

lelithiasiswith

complications,3

3ER

CPs

,and

sphinc

terotomy

W51

115D

7Ye

s0

Cho

lelithiasiswith

complications,2

3ER

CPs

,and

biliarytrac

tstenting

M29

395T

6Ye

s0

Cho

lecystitis,biliaryob

struction,

andch

olec

ystectom

y.Re

fractory

ascites

W18

465T

3Ye

s0

Cho

lelithiasiswith

complications

Ma

2432

5T3

Yes

0Cho

lelithiasiswith

complications

requirin

gER

CP.

Live

rcystd

eroo

fing

M26

355T

3No

0Non

obstructiveintrahepa

ticbiliarytractdu

ctdilationandliver

fibrosis.

Recurre

ntbiliarysepsis

W31

435D

2Ye

s0

Cho

lelithiasiswith

complications.C

holecystec

tomy

Wa

2630

4/5

2Ye

s2

Cho

lelithiasiswith

complications.L

iver

cyst

infections

andhe

morrha

ge

M58

25T

1Ye

s0

Cho

lelithiasiswith

complications

requ

iring

33ER

CPs,sph

incterotom

y,andbiliarytra

ctsten

t

W57

45

1No

0Biliarysepsis

Wa

2132

5D1

Yes

0Cho

lelithiasisan

dbiliarysepsisrequirin

gch

olec

ystectom

y.Su

bphren

icab

scess,liver

cyst

aspira

tion,

cyst

deroo

fing

,and

partia

lhep

atec

tomy

M56

165D

1No

0Biliarysepsis

W52

255T

1Ye

s0

Cho

lelithiasiswith

complications.E

RCP

Wa

6812

31

Yes

0Cho

lelithiasiswith

complications.A

utoimmun

ehe

patitis

W44

105T

1Ye

s0

Cho

lelithiasiswith

complications.E

RCPan

dsp

hinc

terotomy.

Cho

lecystec

tomy

M45

125T

1Ye

s0

Obstructivejaun

dice,

cholec

ystitis

W47

45

1Ye

s0

Cho

lelithiasisrequirin

gER

CPco

mplicated

bypan

crea

titis

W31

313

1Ye

s0

Cho

lecystec

tomy

M28

445D

1Ye

s0

Cho

lecystec

tomy

M:1

1;W:1

3Med

ian31

(IQR,

26–49

)

Med

ian28

(IQR,

12–36

)

Med

ian3

(IQR,

1–8)

83%

(20of

24)

Med

ian0

(IQR,

0–0)

W32

135D

0No

3Live

rcyst

infections.M

assive

polycystic

liver

with

cyst

drainag

e

W41

255T

0No

3Re

curren

tliver

cyst

infections

andliver

abscess

Wa

2422

51

Yes

2Live

rcyst

infections.C

holelithiasis

Wa

486

4/5

1Ye

s2

Live

rcyst

infections.C

holelithiasisrequirin

gch

olec

ystectom

y

W44

55

0No

2Live

rcyst

infections.C

ystderoo

fing

(32)

W30

335D

0No

1Live

rcystinfec

tion.Cho

lelithiasiswith

complications

requirin

g23

ERCPs

andbiliarytract

sten

tinsertio

n

M20

325D

0No

1Live

rcyst

infection

W48

205T

0No

1Live

rcyst

infection

W38

01

0No

0Massive

polycystic

liver

(tran

splanted

)

W36

85T

0No

0Cystaspira

tionan

dderoo

fing

W49

95

0No

0Massive

polycystic

liver

(tran

splanted

)

M:1

;W:1

0Med

ian38

(IQR,

31–46

)

Med

ian13

(IQR,

7–24

)

Med

ian0

(IQR,

0–0)

18%

(2of

11)

Med

ian1

(IQR,

0.5–

2)

Cho

lelithiasiswith

complications

indicates

gallstone

swith

biliarysepsis(cho

lecystitisan

d/orc

holang

itis).W

,wom

an;M

,man

;ERC

P,en

dosco

pic

retrog

radech

olan

giopan

crea

togram;IQR,

interqua

rtile

rang

e.Biliaryco

mplications

werethepredom

inatepresentationin

thefirst24

patientsin

thetable,a

ndliver

complications

predom

inated

intheremaining

11patients.

a Patientswith

bothbiliarytrac

tand

serio

usliver

presentations.Imag

ingwas

available

for4

6%(85of

185)

ofpatientswith

ADPKDon

mainten

ance

RRT:

89%

(76of

85)h

adev

iden

ceof

multip

leliver

cysts,26

%(22

of85

)had

commonbile

duc

tdila

tion,

and16

%(14of

85)h

adgallstone

s.

2740 Journal of the American Society of Nephrology J Am Soc Nephrol 28: 2738–2748, 2017

CLINICAL EPIDEMIOLOGY www.jasn.org

Table 2. Baseline characteristics of patients with polycystic kidney disease versus control populations at date of entry (allEngland HES 1998–2012)

CharacteristicAll Patients Patients with Treated ESRD

Polycystic Kidney Disease Hospital Controls P Value Polycystic Kidney Disease Other ESRD Causes P Value

N 23,454 6,412,754 5813 62,519DemographicsWomen 10,789 (46%) 3,349,541 (52%) ,0.001 2665 (46%) 23,813 (38%) ,0.001Median age (IQR), yr 58 (44–70) 48 (34–67) ,0.001 57 (48–66) 62 (48–73) ,0.00120–30 1679 (7%) 1,140,480 (18%) ,0.001 95 (2%) 3177 (5%) ,0.00130–40 2822 (12%) 1,253,004 (20%) ,0.001 382 (7%) 6078 (10%) ,0.00140–50 3753 (16%) 946,595 (15%) ,0.001 1291 (22%) 8368 (13%) ,0.00150–60 4558 (19%) 862,344 (13%) ,0.001 1689 (29%) 10,527 (17%) ,0.00160–70 4646 (20%) 833,212 (13%) ,0.001 1365 (23%) 14,002 (22%) 0.0670–80 4273 (18%) 847,183 (13%) ,0.001 793 (14%) 14,782 (24%) ,0.001$80 1723 (7%) 529,936 (8%) ,0.001 198 (3%) 5585 (9%) ,0.001

EthnicityWhite 20,011 (85%) 5,209,271 (81%) ,0.001 5086 (87%) 49,059 (78%) ,0.001Nonwhite 2133 (9%) 464,484 (7%) ,0.001 647 (11%) 12,233 (20%) ,0.001Unknown 1310 (6%) 738,999 (12%) ,0.001 80 (1%) 1227 (2%) 0.002

Quintiles of IMD scoreQuintile 1, lowest 3714 (16%) 979,301 (15%) 0.02 998 (17%) 8323 (13%) ,0.001Quintile 2 5253 (22%) 1,401,590 (22%) 0.05 1348 (23%) 12,181 (19%) ,0.001Quintile 3 5015 (21%) 1,395,153 (22%) 0.17 1202 (21%) 13,197 (21%) 0.44Quintile 4 4931 (21%) 1,357,995 (21%) 0.57 1227 (21%) 14,041 (22%) 0.02Quintile 5, highest 4541 (19%) 1,278,715 (20%) 0.03 1038 (18%) 14,777 (24%) ,0.001

Region of residencyEast Midlands 1810 (8%) 397,065 (6%) ,0.001 414 (7%) 3986 (6%) 0.03East of England 2020 (9%) 578,715 (9%) 0.03 587 (10%) 5222 (8%) ,0.001Northeast 397 (2%) 122,249 (2%) 0.02 92 (2%) 820 (1%) 0.08Northwest 1111 (5%) 325,304 (5%) 0.02 247 (4%) 2368 (4%) 0.08Southeast 2910 (12%) 703,644 (11%) ,0.001 703 (12%) 6563 (10%) 0.001Southwest 1525 (7%) 447,399 (7%) 0.01 376 (6%) 3670 (6%) 0.06West Midlands 807 (3%) 251,870 (4%) 0.001 245 (4%) 2541 (4%) 0.58Yorkshire and Humber 203 (1%) 81,723 (1%) ,0.001 59 (1%) 635 (1%) .0.99Other 12,671 (54%) 3,504,785 (55%) 0.05 3090 (53%) 36,714 (59%) ,0.001

Year of entry1998 4979 (21%) 1,032,212 (16%) ,0.0011999 3661 (16%) 959,561 (15%) 0.012000 2613 (11%) 740,815 (12%) 0.05 563 (10%) 5363 (9%) 0.0042001 2039 (9%) 591,746 (9%) ,0.01 473 (8%) 4855 (8%) 0.312002 1705 (7%) 504,447 (8%) 0.001 480 (8%) 4737 (8%) 0.062003 1505 (6%) 447,877 (7%) 0.001 458 (8%) 4700 (8%) 0.322004 1246 (5%) 387,909 (6%) ,0.001 413 (7%) 4679 (7%) 0.292005 1070 (5%) 335,854 (5%) ,0.001 426 (7%) 4721 (8%) 0.542006 964 (4%) 295,583 (5%) 0.001 447 (8%) 5222 (8%) 0.082007 868 (4%) 267,603 (4%) 0.001 526 (9%) 5484 (9%) 0.482008 823 (4%) 246,447 (4%) 0.01 512 (9%) 5421 (9%) 0.722009 726 (3%) 219,299 (3%) 0.01 453 (8%) 5626 (9%) 0.0022010 619 (3%) 192,632 (3%) 0.001 487 (8%) 5509 (9%) 0.262011 503 (2%) 155,615 (2%) 0.01 486 (8%) 5102 (8%) 0.592012 133 (1%) 35,154 (1%) 0.70 89 (2%) 1100 (2%) 0.20

ComorbiditiesDiabetes 906 (4%) 189,858 (3%) ,0.001 470 (8%) 20,119 (32%) ,0.001Vascular 1747 (7%) 181,832 (3%) ,0.001 765 (13%) 16,820 (27%) ,0.001Cancer 681 (3%) 77,098 (1%) ,0.001 245 (4%) 5321 (9%) ,0.001

Data are n, n (%), or median (IQR). The hospital controls were individuals who had been admitted to the hospital for any one of a wide range of minor medical orsurgical conditions across 12 years (excluding any patient with polycystic kidney disease). These included admissions with diagnoses of squint, cataracts, otitisexterna/media, varicose veins, hemorrhoids, upper respiratory tract infections, nasal polyps, teeth disorders, nail diseases, sebaceous cyst, soft tissue kneecomplaints, bunions, contraceptive advice, limb fractures, dislocations sprains and strains, minor head injury and superficial injuries or contusions, and operations,including appendiectomy, dilation and curettage, primary lower limb arthroplasties, tonsillectomy, and adenoidectomy. IQR, interquartile range.

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adjusted rates and ADPKD versus non-ADPKD RRs for arange of other known manifestations of ADPKD. These in-clude cerebral aneurysms, inguinal and other abdominal wallhernias, urinary tract infections, cardiac valve disease, and di-verticular disease (Supplemental Table 2 provides outcomedefinitions), all of which were positively associated withADPKD.

Compared with hospital controls, the rates of admissionfor biliary tract disease were 2.2 times higher in people withADPKD (1.31% versus 0.59% per year; RR, 2.24; 95% CI,2.16 to 2.33) and 4.7 times higher for serious liver compli-cations (0.31% versus 0.07% per year; RR, 4.67; 95%CI, 4.35to 5.02) (Figure 1A). These equate to an absolute excess riskof biliary tract disease associated with ADPKD of 0.73% peryear (95% CI, 0.68% to 0.78% per year), which was largerthan the absolute excess risk for serious liver disease (0.24%per year; 95% CI, 0.21% to 0.28% per year), cerebral aneu-rysms (0.11% per year; 95% CI, 0.09% to 0.14% per year),inguinal hernias (0.11% per year; 95% CI, 0.08% to 0.14%per year), or abdominal wall hernias (0.35% per year;95% CI, 0.32% to 0.38% per year); similar to the excess riskfor colonic diverticular disease (0.73% per year; 95% CI,0.67% to 0.79% per year); and much less than for urinarytract infections (2.20% per year; 95% CI, 2.10% to 2.31%per year).

On average, hospital controls are likely to have better kidneyfunction than people with ADPKD, which is important toconsider in secondary analyses, because CKD might mediatesome of the positive associations between ADPKD and out-comes. We, therefore, repeated analyses just among the 68,332people who had started maintenance RRT, which effectivelyadjusts for any effect of advanced CKD.

Within the treated ESRD population, 9% (5813 of 68,332)were recorded as having ADPKD. People with ESRD due toADPKD were, on average, younger (57 versus 62 years old),more likely to be women (46% versus 38%), and less likely tohave a history of prior diabetes (8% versus 32%) or vasculardisease (13% versus 27%) than those with ESRD due to othercauses (Table 2).

After restricting analyses to those with treated ESRD,ADPKD versus non-ADPKD RRs for the positive control dis-eases were attenuated (Figure 1B). Nevertheless, comparedwith those with other causes of ESRD, rates of hospitalizationamong people with ADPKDwere 2.2 times higher for cerebralaneurysms (0.13% versus 0.06% per year; RR, 2.23; 95% CI,1.53 to 3.26), 2.5 times higher for other abdominal wall her-nias (1.23% versus 0.50% per year; RR, 2.47; 95% CI, 2.19 to2.80), and about 60%–70% higher for both inguinal hernias(1.00% versus 0.59% per year; RR, 1.70; 95% CI, 1.49 to 1.95),and colonic diverticular disease (2.70% versus 1.64% per year;RR, 1.65; 95% CI, 1.52 to 1.79) (Figure 1B). Rates forserious cardiac valve disease, however, were similar amongpeople with ESRD due to ADPKD and people with othercauses of ESRD (1.47% versus 1.63% per year; RR, 0.90;95% CI, 0.81 to 1.00).

The RRs for biliary tract disease and serious liver com-plications were also substantially attenuated when analyseswere restricted to those with treated ESRD, but ADPKDremained positively associated with biliary tract disease.Compared with those with other causes of ESRD, rates ofbiliary tract disease were 19% higher among people withADPKD (1.92% versus 1.61% per year; RR, 1.19; 95% CI,1.08 to 1.31) and 15% higher for serious liver complications(0.70% versus 0.62% per year; RR, 1.15; 95% CI, 0.98 to1.33) (Figure 1B).

Among people on maintenance RRT, the absolute excessrisk of biliary tract complications (0.31% per year; 95% CI,0.13% to 0.49% per year) in people with ADPKD remainedlarger than for serious liver complications (0.09% per year;95% CI, 20.02% to 0.2% per year) and cerebral aneurysms(0.07% per year; 95% CI, 0.03% to 0.12% per year); becamesimilar to the absolute excess risk for inguinal hernias (0.41%per year; 95% CI, 0.29% to 0.54% per year); and was some-what smaller than for other abdominal wall hernias (0.73%per year; 95% CI, 0.59% to 0.87% per year), colonic divertic-ular disease (1.06% per year; 95% CI, 0.85% to 1.27% peryear), and urinary tract infections (1.36% per year; 95% CI,1.01% to 1.72% per year).

In analyses performed separately for different age groupsand by sex, compared with hospital controls, ADPKD versusnon-ADPKD RRs for serious liver complications were higherin women than in men (heterogeneity P,0.001), confirmingthe observation from our case series. However, the reverse wasobserved for biliary tract disease (heterogeneity P,0.001)(Figure 2A). RRs for serious liver disease were larger amongyounger people with ADPKD (trend P,0.001), but the reversewas also true for biliary tract disease (trend P,0.001) (Figure2A). In analyses restricted to people with treated ESRD,ADPKD versus non-ADPKD RRs for biliary tract disease be-came similar in both sexes (heterogeneity P=0.22), but RRs forserious liver complications remained higher in women than inmen (heterogeneity P,0.001) (Figure 2B). There was no dif-ference in RRs for either complication by age in people withtreated ESRD (Figure 2B).

In sensitivity analyses, results were similar when repeatedwith the exclusion of secondary diagnoses to define diseaseoutcomes (Supplemental Figures 3 and 4) or the exclusionof people with a serious liver complication (which reducesany overascertainment of biliary tract disease identifiedincidentally during any liver investigations; data notshown).

Cause-Specific Mortality among People with ADPKDBiliary tract or liver disease is an uncommon underlying causeof death among people with ADPKD, except among those whowere hospitalized in the cohort for either biliary tract disease orserious liver complications, in whom it accounted for 8% ofdeaths (Supplemental Figure 5). This proportion was similarin women and men (9% versus 6%, respectively; P=0.06)(Supplemental Figure 6).

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Figure 1. Association between polycystic kidney disease and risk of hospitalization for different diseases in all England HES 199822012. Allpatients (A) or limited to those treated for end-stage renal disease (B). Outcomes include admissions with relevant diagnostic codes in anydiagnostic position or any relevant procedural codes. Adjusted for age at entry as a continuous variable (using both linear and quadratic terms),sex, ethnicity, quintile of patients’ IMD score, region of residence, calendar year of first recorded admission (or year of RRT start), and co-morbidities (grouped into vascular, cancer, and diabetes). RRs for aortic or other aneurysms are 3.74 (95% CI, 3.53 to 3.97) for all patients and0.96 (95% CI, 0.84 to 1.11) for patients with treated ESRD. RRs for hiatus hernia and gastroesophageal reflux disease are 1.58 (95% CI, 1.53 to1.63) for all patients and 1.03 (95% CI, 0.95 to 1.12) for patients with treated ESRD. RRs for renal stones are 4.63 (95% CI, 4.39 to 4.87) for allpatients and 0.96 (95% CI, 0.81 to 1.15) for patients with treated ESRD. RRs for breast cancer (negative control) are 1.00 (95% CI, 0.88 to 1.12)for all patients and 0.62 (95% CI, 0.45 to 0.86) for patients with treated ESRD.

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Figure 2. Association between polycystic kidney disease and risk of hospitalization for biliary tract and serious liver complications by age andsex in all England HES 199822012. All patients (A) or limited to those treated for end-stage renal disease (B). Outcomes include admissionswith relevant diagnostic codes in any diagnostic position or any relevant procedural codes. Adjusted for age at entry as a continuousvariable (using both linear and quadratic terms), sex, ethnicity, quintile of patients’ IMD score, region of residence, calendar year of firstrecorded admission (or year of RRT start), and comorbidities (grouped into vascular, cancer, and diabetes). Het, heterogeneity.

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DISCUSSION

We have reported a case series and a large disease associationstudy including over 23,000 patients with ADPKD. Our caseseries findings suggested that biliary tract disease is as frequentinpeoplewithADPKDas serious liver complications and that ithas a distinct clinical presentation and sex distribution. Ourdisease association study confirmed that hospitalization forbiliary tract disease is more common among people withADPKD than people without and that the absolute excessrisk was larger than for serious liver complications and a rangeof other better described extrarenal manifestations of ADPKD.

The Halt Progression of Polycystic Kidney Disease Study A(HALT-PKD-A) has characterized the biliary tract and liverimaging features of ADPKD.23 Common bile duct dilationwaspresent in 17% of the cohort, but it was the only biliary tractabnormality described. These data corroborate earlier obser-vations from a Japanese study of 55 people with ADPKD,where the prevalence of common bile duct dilation was 40%compared with 7% in controls.12 A higher prevalence of com-mon bile duct dilation in the Japanese study may be accountedfor by more advanced ADPKD, because one half of the Japa-nese patients with ADPKD had started hemodialysis, whereasall HALT-PKD-A participants had an estimated glomerularfiltration rate .60 ml/min per 1.73 m2. In addition to thesestudies, our systematic literature review identified a few casereports of biliary tract complications in ADPKD (Supplemen-tal Figure 1),12,14–16 but no study assessed if there was an excessrisk of clinically significant biliary tract disease associated withADPKD. The presented results, therefore, represent the firstquantification of the association between ADPKD and seriousbiliary tract disease.

Another important finding in both our case series and dis-ease association study is that the relative sizes of the ADPKDversus non-ADPKD RRs for serious liver complications werehigher among women than men, but the reverse was true forbiliary tract disease associations. Other ADPKD studies, in-cluding the HALT-PKD-A, have also found that the prevalenceof liver cysts is higher in women with ADPKD compared withmen.9,23 Estrogen receptors are expressed in the epithelium ofliver cysts,1,8,24,25 and in women, exogenous estrogen use andpregnancy both seem to increase cyst cell proliferation andliver cyst size.1,8,24,25 However, liver enlargement in ADPKDresults from both cystic change and increased liver parenchy-mal volume, and men with ADPKD have been found to haverelatively increased height-adjusted liver parenchymal volumecompared to women.23 The differing patterns of associationsin our subgroup analyses by age and sex suggest that cysticchange in the liver—which has been reported to cause ob-structive jaundice17–22—is not the key cause of biliary tractcomplications in ADPKD. Polycystin complexes localize toprimary cilia in the kidney and biliary tract. In the biliarytract, cilia may act as mechanosensors, maintaining thedifferentiated state of cholangiocyte epithelia and detectingchanges in bile flow and composition.26,27 Mutations in

polycystin-encoding genes in ADPKD may, therefore, affectcholangiocyte cilia, resulting in abnormal bile tract function(with biliary stasis and duct dilation) and/or bile duct glandcyst formation.15,28 A shared biliary phenotype between mu-tations that cause autosomal recessive and ADPKD has alsobeen suggested.29–31

Biliary tract disease has featured in the results of recentrandomized trials of treatments aimed at inhibiting renalcyst cell proliferation and fluid secretion. In a trial of a somato-statin analog, ocreotide, the rate of kidney volume increasewasslowed compared with placebo,32 and post hoc analyses sug-gested that octreotide may also reduce liver parenchyme andcyst expansion.33 However, it also led to increased numbers ofnonserious reports of gallstones (octreotide: ten of 40 [25%]versus placebo: zero of 39 [0%]) and biliary sand (octreotide:seven of 40 [18%] versus placebo: one of 39 [3%]). The tworeported serious cases of acute cholecystitis in this study wereboth among those allocated octreotide.32 These results areconsistent with previous reports of octreotide-associated gall-stones, which are attributed to reduced postprandial gallblad-der contractility and biliary stasis (indicated by increasedfasting gallbladder volumes).34 Octreotide exerts its beneficialeffects on cysts through inhibition of the secondary messengercyclic adenosine monophosphate in biliary epithelial cells.However, inhibiting this pathway with the vasopressin V2-receptor blocker, tolvaptan, significantly reduces the rate of in-crease in total kidney volume compared with placebo withoutany reported excess of upper abdominal pain, gallstones, orbiliary tract adverse events.35

Although not our primary aim, these data represent thelargest confirmatory study of the size of associations betweenADPKD and a range of previously described extrarenal man-ifestations.8,36 Interestingly, we also found that, despite aknown increased prevalence of incompetent mitral and aorticvalves in ADPKD,37 after taking account of renal function,serious cardiac valve disease was no more common in peoplewith ADPKD and ESRD than in those with other causes ofESRD. These findings may influence how nephrologists coun-sel patients with ADPKD. Testing other hypotheses, we alsofound no evidence that ADPKD was associated with increasedrisk of hospitalization with gastroesophageal reflux disease,renal stones, or aortic aneurysms among those with treatedESRD (Figure 1 footnote).

This study uses big data to test bedside observations madeover approximately 50 years, but there are certain limitations.First, predialysis CKD stages are not well recorded in HES, andthere is no informationon laboratory data; therefore, it was notpossible to assess comprehensively how much reduced renalfunction may explain associations with ADPKD. However,HES can be used to identify treated ESRD, and analyses focusedonmaintenance RRTeffectively adjust for advanced CKD, par-tially overcoming this limitation. Secondly, no information onbody mass index—which has been positively associated withcholelithiasis—was available for adjustment. Thirdly, distin-guishing sources of infection in admissions for sepsis is often

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difficult, and therefore, rates of infection from particularsources may be underestimates. Lastly, ADPKD definitionswere not directly confirmed. Nevertheless, excellent agree-ment between nurse-recorded primary renal diagnosis andADPKD recorded in HES data has been shown previously,and therefore, any misclassification is unlikely to have led tomuch underestimation in the size of RRs.38,39

In summary, we raised and tested the hypothesis thatADPKD is associated with clinically significant biliary tractdisease as well as serious liver complications. We found thatwomen with ADPKD are at higher relative risk of a liver com-plication than men, but the reverse was observed for the pos-itive association between ADPKD and biliary tract disease,suggesting that liver and biliary complications of ADPKDhave distinct disease mechanisms. The absolute excess risksof biliary tract complications in people with ADPKD are sim-ilar to the absolute excess risks of some of the better establishedcomplications, and therefore, biliary tract disease should be akey differential diagnosis in patients with ADPKD presentingwith abdominal pain or sepsis.

CONCISE METHODS

Oxford Kidney Unit Case Series (1967–2015)All patientswithpresumedADPKDcared for by theOxfordKidneyUnit

between1967andAugust of2015were included.Biliary tract disease and

serious liver complications were ascertained by systematic physician

review of diagnoses, procedures, and investigation reports on the unit’s

electronic patient record system and local radiology, microbiology, and

histopathology systems. After identified, detailed information on each

biliary tract disease or serious liver complication was extracted by med-

ical notes review, which included demographics, age and renal status at

the time of the complication, details of the clinical presentation, includ-

ing microbiologic findings, and clinical management.

Disease Association Study Using All England HospitalEpisode Statistics (1998–2012)Ethical approval for analysis of the record linkage study data was

obtained from the Central and South Bristol Multi-Centre Research

Ethics Committee (04/Q2006/176). We used anonymized linked all

England HES inpatient records with additional linkage to national

mortality records.40 Since 1998, HES have recorded information on

all hospital inpatient activity in England, including dates of admission

and discharge; demographics (including age, sex, and ethnicity);

measures of social deprivation; the primary diagnostic reason for

admission with relevant secondary diagnoses coded using the Inter-

national Statistical Classification of Diseases and Related Health

Problems Revision 10 (ICD-10)41; and all procedures coded using

the Office of Population Censuses and Surveys Classification of Sur-

gical Operations and Procedures (OPCS), version 4.

Identification of Patients with ADPKDA patient with any mention of ICD-10 codes Q61.2 or Q61.3 in HES

was presumed to have a diagnosis of ADPKD. The validity of using

these codes has been directly shownpreviously as part of a clinical trial

among patients with kidney transplants, in which there was an excel-

lent level of agreement (k statistic .0.9) between nurse-reported

primary renal diagnosis of cystic kidney disease and ADPKD coded

in HES.38,39 To reduce the chances of including autosomal recessive

polycystic kidney disease in analyses, people hospitalized or starting

RRT before 20 years of age were excluded.

Identification of Control PopulationsTwo control populations with no mention of ADPKD codes in

any admission were derived from HES. The first was a large

group of patients admitted for minor diagnoses or procedures (a

complete list is in Table 2). The second was any patient who was

treated with maintenance RRT (i.e., long-term dialysis or kidney

transplant) for ESRD and survived for at least 90 days from the start

of RRT.

OutcomesOutcomes for relevant diseases were identified using information

encoded in any diagnostic position (primary or secondary) or any

recorded procedure. These included (1) treated ESRD; (2) a group

of other positive control diseases that have previously been report-

ed to be extrarenal manifestations of ADPKD8,36 (including com-

plications or treatment of cerebral aneurysms, abdominal wall

hernias [separated into inguinal and other], urinary tract infec-

tions, serious cardiac valve disease, and colonic diverticular dis-

ease); (3) a group of liver diagnoses and procedures associated

with ADPKD, including liver abscess and liver deroofing,

resection, and transplantation; (4) biliary tract diagnoses and pro-

cedures, including cholecystitis, biliary tract stones, and cholecys-

tectomy (Supplemental Table 2 has full list of ICD-10 and OPCS

codes used to define outcomes); and (5) a negative control disease

(breast cancer), which has previously been reported as not asso-

ciated with ADPKD.42 In addition, sensitivity analyses were per-

formed excluding diagnostic information recorded as secondary

diagnoses and after excluding people who ever had a serious liver

complication.

CovariatesThe following patient characteristics were extracted from HES: age,

sex, ethnicity (white, nonwhite, and unknown), region of residence,

English Index of Multiple Deprivation (IMD) score,43 and comor-

bidity (diabetes, vascular, or cancer considered separately). For hos-

pital control analyses, comorbidity was derived from diagnoses and

procedures recorded on the first admission. For the ESRD cohort,

comorbidity was derived from the date of the start of RRT and any

admission in the preceding 2 years.

Statistical MethodsBaseline characteristics for each derived cohort were expressed as

numbers (percentages) or medians (interquartile ranges) and com-

pared with standard chi-squared or Kruskal–Wallis tests, respectively.

The follow-up time for each outcome began from the index date

(defined as the date of the first admission) and ended at the earliest

of date of a relevant outcome, death, or end of the cohort follow-up

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(March 31, 2012). Rates for each outcome were then calculated using

Poisson regression adjusted for age as a continuous variable (using

both linear and quadratic terms), sex, ethnicity (three groups as

above), quintiles of IMD score, region of residence (nine groups),

prior reported diabetes, vascular disease (excluding subarachnoid

hemorrhage), or cancer (excluding breast cancer). Changes in coding

practice over timewere controlled for by adjustment for calendar year

of first admission (or where relevant, year of start of maintenance

RRT).

Primary analyses compared patients with ADPKD with gen-

eral hospital controls to quantify the full effect of ADPKD on

risk of outcomes. Secondarily, we assessed how much advanced

CKD may affect ADPKD versus non-ADPKD RRs by repeating

analyses only among those who had already started RRT for

ESRD (with the index date increased to the date of start of main-

tenance RRT).

RRs and their 95% CIs were calculated using standard statistical

methods. Separate ADPKD versus non-ADPKD RRs for men and

women and by age groups were calculated and compared using stan-

dard tests forheterogeneity and trend, respectively.Analyses usedSAS,

version 9.3 (SAS Institute, Cary, NY) and R version 3.2.1 (www.

r-project.org).

ACKNOWLEDGMENTS

We acknowledge the large number of coders and technicians who

have created and curated Hospital Episode Statistics. This study was

supported by core-funding to the Medical Research Council-

PopulationHealthResearchUnit and theClinicalTrial ServiceUnit and

Epidemiological Studies Unit (CTSU), University of Oxford.

DISCLOSURESThe Medical Research Council–Population Health Research Unit receives

core funding from the United KingdomMedical Research Council. The CTSU

receives funding from the British Heart Foundation and Cancer Research

United Kingdom. The CTSU has a staff policy of not accepting honoraria or

other payments from the pharmaceutical industry, expect for the reimburse-

ment of costs to participate in scientific meetings (www.ctsu.ox.ac.uk).

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This article contains supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2017010084/-/DCSupplemental.

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